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Mitochondrial genetic background modifies the relationship between traffic-related air pollution exposure and systemic biomarkers of inflammation.
ABSTRACT: Mitochondria are the main source of reactive oxygen species (ROS). Human mitochondrial haplogroups are linked to differences in ROS production and oxidative-stress induced inflammation that may influence disease pathogenesis, including coronary artery disease (CAD). We previously showed that traffic-related air pollutants were associated with biomarkers of systemic inflammation in a cohort panel of subjects with CAD in the Los Angeles air basin.We tested whether air pollutant exposure-associated inflammation was stronger in mitochondrial haplogroup H than U (high versus low ROS production) in this panel (38 subjects and 417 observations).Inflammation biomarkers were measured weekly in each subject (? 12 weeks), including interleukin-6 (IL-6), tumor necrosis factor-? (TNF-?), C-reactive protein, interleukin-6 soluble receptor and tumor necrosis factor-soluble receptor II. We determined haplogroup by restriction fragment length polymorphism analysis. Air pollutants included nitrogen oxides (NOx), carbon monoxide (CO), organic carbon, elemental and black carbon (EC, BC); and particulate matter mass, three size fractions (<0.25 µm, 0.25-2.5 µm, and 2.5-10 µm in aerodynamic diameter). Particulate matter extracts were analyzed for organic compounds, including polycyclic aromatic hydrocarbons (PAH), and in vitro oxidative potential of aqueous extracts. Associations between exposures and biomarkers, stratified by haplogroup, were analyzed by mixed-effects models.IL-6 and TNF-? were associated with traffic-related air pollutants (BC, CO, NOx and PAH), and with mass and oxidative potential of quasi-ultrafine particles <0.25 µm. These associations were stronger for haplogroup H than haplogroup U.Results suggest that mitochondrial haplogroup U is a novel protective factor for air pollution-related systemic inflammation in this small group of subjects.
Project description:Gene expression changes are linked to air pollutant exposures in in vitro and animal experiments. However, limited data are available on how these outcomes relate to ambient air pollutant exposures in humans. We performed an exploratory analysis testing whether gene expression levels were associated with air pollution exposures in a Los Angeles area cohort of elderly subjects with coronary artery disease. Candidate genes (35) were selected from published studies of gene expression-pollutant associations. Expression levels were measured weekly in 43 subjects (? 12 weeks) using quantitative PCR. Exposures included gaseous pollutants O3, nitrogen oxides (NOx), and CO; particulate matter (PM) pollutants elemental and black carbon (EC, BC); and size-fractionated PM mass. We measured organic compounds from PM filter extracts, including polycyclic aromatic hydrocarbons (PAHs), and determined the in vitro oxidative potential of particle extracts. Associations between exposures and gene expression levels were analyzed using mixed-effects regression models. We found positive associations of traffic-related pollutants (EC, BC, primary organic carbon, PM 0.25-2.5 PAH and/or PM 0.25 PAH, and NOx) with NFE2L2, Nrf2-mediated genes (HMOX1, NQO1, and SOD2), CYP1B1, IL1B, and SELP. Findings suggest that NFE2L2 gene expression links associations of traffic-related air pollution with phase I and II enzyme genes at the promoter transcription level.
Project description:High concentrations of air pollutants on roadways, relative to ambient concentrations, contribute significantly to total personal exposure. Estimation of these exposures requires measurements or prediction of roadway concentrations. Our study develops, compares, and evaluates linear regression and nonlinear generalized additive models (GAMs) to estimate on-road concentrations of four key air pollutants, particle-bound polycyclic aromatic hydrocarbons (PB-PAH), particle number count (PNC), nitrogen oxides (NOx), and particulate matter with diameter <2.5 ?m (PM2.5) using traffic, meteorology, and elevation variables. Critical predictors included wind speed and direction for all the pollutants, traffic-related variables for PB-PAH, PNC, and NOx, and air temperatures and relative humidity for PM2.5. GAMs explained 50%, 55%, 46%, and 71% of the variance for log or square-root transformed concentrations of PB-PAH, PNC, NOx, and PM2.5, respectively, an improvement of 5% to over 15% over the linear models. Accounting for temporal autocorrelation in the GAMs further improved the prediction, explaining 57-89% of the variance. We concluded that traffic and meteorological data are good predictors in estimating on-road traffic-related air pollutant concentrations and GAMs perform better for nonlinear variables, such as meteorological parameters.
Project description:Exposure-response information about particulate air-pollution constituents is needed to protect sensitive populations. Particulate matter <2.5 mm (PM2.5) components may induce oxidative stress through reactive-oxygen-species generation, including primary organics from combustion sources and secondary organics from photochemically oxidized volatile organic compounds. We evaluated differences in airway versus systemic inflammatory responses to primary versus secondary organic particle components, particle size fractions, and the potential of particles to induce cellular production of reactive oxygen species.A total of 60 elderly subjects contributed up to 12 weekly measurements of fractional exhaled nitric oxide (NO; airway inflammation biomarker), and plasma interleukin-6 (IL-6; systemic inflammation biomarker). PM2.5 mass fractions were PM0.25 (<0.25 ?m) and PM0.25-2.5 (0.25-2.5 ?m). Primary organic markers included PM2.5 primary organic carbon, and PM0.25 polycyclic aromatic hydrocarbons and hopanes. Secondary organic markers included PM2.5 secondary organic carbon, and PM0.25 water soluble organic carbon and n-alkanoic acids. Gaseous pollutants included carbon monoxide (CO) and nitrogen oxides (NOx; combustion emissions markers), and ozone (O3; photochemistry marker). To assess PM oxidative potential, we exposed rat alveolar macrophages in vitro to aqueous extracts of PM0.25 filters and measured reactive-oxygen-species production. Biomarker associations with exposures were evaluated with mixed-effects models.Secondary organic markers, PM0.25-2.5, and O3 were positively associated with exhaled NO. Primary organic markers, PM0.25, CO, and NOx were positively associated with IL-6. Reactive oxygen species were associated with both outcomes.Particle effects on airway versus systemic inflammation differ by composition, but overall particle potential to induce generation of cellular reactive oxygen species is related to both outcomes.
Project description:Short-term exposure to ambient air pollution has been associated with acute increases in cardiovascular hospitalization and mortality. However, causative chemical components and underlying pathophysiological mechanisms remain to be clarified. We hypothesized that endothelial dysfunction would be associated with mobile-source (traffic) air pollution and that pollutant components with higher oxidative potential to generate reactive oxygen species (ROS) would have stronger associations.We carried out a cohort panel study in 93 elderly non-smoking adults living in the Los Angeles metropolitan area, during July 2012-February 2014. Microvascular function, represented by reactive hyperemia index (RHI), was measured weekly for up to 12 weeks (N?=?845). Air pollutant data included daily data from regional air-monitoring stations, five-day average PM chemical components and oxidative potential in three PM size-fractions, and weekly personal nitrogen oxides (NOx). Linear mixed-effect models estimated adjusted changes in microvascular function with exposure.RHI was inversely associated with traffic-related pollutants such as ambient PM2.5 black carbon (BC), NOx, and carbon monoxide (CO). An interquartile range change increase (1.06 ?g/m(3)) in 5-day average BC was associated with decreased RHI, -0.093 (95 % CI: -0.151, -0.035). RHI was inversely associated with other mobile-source components/tracers (polycyclic aromatic hydrocarbons, elemental carbon, and hopanes), and PM oxidative potential as quantified in two independent assays (dithiothreitol and in vitro macrophage ROS) in accumulation and ultrafine PM, and transition metals.Our findings suggest that short-term exposures to traffic-related air pollutants with high oxidative potential are major components contributing to microvascular dysfunction.
Project description:A mobile monitoring platform developed at the University of Washington Center for Clean Air Research (CCAR) measured 10 pollutant metrics (10 s measurements at an average speed of 22 km/hr) in two neighborhoods bordering a major interstate in Albuquerque, NM, USA from April 18-24 2012. 5 days of data sharing a common downwind orientation with respect to the roadway were analyzed. The aggregate results show a three-fold increase in black carbon (BC) concentrations within 10 meters of the edge of roadway, in addition to elevated nanoparticle concentration and particulate matter with aerodynamic diameter < 1 ?m (PN1) concentrations. A 30% reduction in ozone concentration near the roadway was observed, anti-correlated with an increase in the oxides of nitrogen (NOx). In this study, the pollutants measured have been expanded to include polycyclic aromatic hydrocarbons (PAH), particle size distribution (0.25-32 ?m), and ultra-violet absorbing particulate matter (UVPM). The raster sampling scheme combined with spatial and temporal measurement alignment provide a measure of variability in the near roadway concentrations, and allow us to use a principal component analysis to identify multi-pollutant features and analyze their roadway influences.
Project description:Natural emissions of air pollutants from the surface play major roles in air quality and climate change. In particular, nitrogen oxides (NOx) emitted from soils contribute ~15% of global NOx emissions, sea salt aerosols are a major player in the climate and chemistry of the marine atmosphere, and biogenic emissions are the dominant source of non-methane volatile organic compounds at the global scale. These natural emissions are often estimated using nonlinear parameterizations, which are sensitive to the horizontal resolutions of inputted meteorological and ancillary data. Here we use the HEMCO model to compute these emissions worldwide at horizontal resolutions of 0.5° lat.?×?0.625° lon. for 1980-2017 and 0.25° lat.?×?0.3125° lon. for 2014-2017. We further offer the respective emissions at lower resolutions, which can be used to evaluate the impacts of resolution on estimated global and regional emissions. Our long-term high-resolution emission datasets offer useful information to study natural pollution sources and their impacts on air quality, climate, and the carbon cycle.
Project description:Background:Air pollution exposures are novel contributors to the growing childhood obesity epidemic. One possible mechanism linking air pollution exposures and obesity is through changes in food consumption patterns. Objective:The aim of this study was to examine the longitudinal association between childhood exposure to air pollutants and changes in diet among adolescents. Design:School-age children were enrolled in the Southern California Children's Health Study during 1993-1994 (n = 3100) and were followed for 4-8 y. Community-level regional air pollutants [e.g., nitrogen dioxide (NO2), elemental carbon (EC), and fine particles with aerodynamic diameter <2.5 µm (PM2.5)] were measured at central monitoring stations. Line dispersion modeling was used to estimate concentrations of traffic-related air pollutants based on nitrogen oxides (NOx) at participants' residential addresses. In addition, self-reported diet information was collected annually using a structured youth/adolescent food-frequency questionnaire during 1997-2001. Generalized linear mixed-effects models were used in the association analyses. Results:Higher exposures to regional and traffic-related air pollutants were associated with intake of a high-trans-fat diet, after adjusting for confounders including socioeconomic status and access to fast food in the community. A 2-SD (12.2 parts per billion) increase in regional NO2 exposure was associated with a 34% increased risk of consuming a high-trans-fat diet compared with a low-trans-fat diet (OR: 1.34; 95% CI: 1.05, 1.72). In addition, higher exposures to acid vapor, EC, PM2.5, and non-freeway NOx were all associated with higher consumption of dietary trans fat (all P < 0.04). Notably, higher exposures to regional NO2, acid vapor, and EC were also associated with a higher consumption of fast food (all P < 0.05). Conclusions:Childhood exposures to regional and traffic-related air pollutants were associated with increased consumption by adolescents of trans fat and fast foods. Our results indicate that air pollution exposures may contribute to obesogenic behaviors. This study was registered at clinicaltrials.gov as NCT03379298.
Project description:Numerous studies have associated air pollutant exposures with adverse birth outcomes, but there is still relatively little information to attribute effects to specific emission sources or air toxics. We used three exposure data sources to examine risks of preterm birth in Los Angeles women when exposed to high levels of traffic-related air pollutants--including specific toxics--during pregnancy.We identified births during 6/1/04-3/31/06 to women residing within five miles of a Southern California Air Quality Management District (SCAQMD) Multiple Air Toxics Exposure Study (MATES III) monitoring station. We identified preterm cases and, using a risk set approach, matched cases to controls based on gestational age at birth. Pregnancy period exposure averages were estimated for a number of air toxics including polycyclic aromatic hydrocarbons (PAHs), source-specific PM2.5 (fine particulates with aerodynamic diameter less than 2.5 ?m) based on a Chemical Mass Balance model, criteria air pollutants based on government monitoring data, and land use regression (LUR) estimates of nitric oxide (NO), nitrogen dioxide (NO2) and nitrogen oxides (NOx). Associations between these metrics and odds of preterm birth were estimated using conditional logistic regression.Odds of preterm birth increased 6-21% per inter-quartile range increase in entire pregnancy exposures to organic carbon (OC), elemental carbon (EC), benzene, and diesel, biomass burning and ammonium nitrate PM2.5, and 30% per inter-quartile increase in PAHs; these pollutants were positively correlated and clustered together in a factor analysis. Associations with LUR exposure metrics were weaker (3-4% per inter-quartile range increase).These latest analyses provide additional evidence of traffic-related air pollution's impact on preterm birth for women living in Southern California and indicate PAHs as a pollutant of concern that should be a focus of future studies. Other PAH sources besides traffic were also associated with higher odds of preterm birth, as was ammonium nitrate PM2.5, the latter suggesting potential importance of secondary pollutants. Future studies should focus on accurate modeling of both local and regional spatial and temporal distributions, and incorporation of source information.
Project description:Acetylation is an important post translational modification of histone that plays a role in regulation of physiological and pathological process in the body. We have recently shown that the inhibition of histone deacetylases (HDAC) by low concentrations of HDAC inhibitors (HDACis), belinostat (up to 0.25 µM) and panobinostat (up to 0.04 µM) promote histone acetylation (e.g., AcH4) and neutrophil extracellular trap formation (NETosis). Clinical use of belinostat and panobinostat often leads to neutropenia and the in vivo concentrations vary with time and tissue locations. However, the effects of different concentrations of these HDACis on neutrophil death are not fully understood. We considered that increasing concentrations of belinostat and panobinostat could alter the type of neutrophil death. To test this hypothesis, we treated human neutrophils with belinostat and panobinostat in the presence or absence of agonists that promote NOX-dependent NETosis (phorbol myristate acetate or lipopolysaccharide from Escherichia coli 0128) and NOX-independent NETosis (calcium ionophores A23187 or ionomycin from Streptomyces conglobatus). Increasing concentrations of HDACis induced histone acetylation in a dose-dependent manner. ROS analyses showed that increasing concentrations of HDACis, increased the degree of NOX-derived ROS production. Higher levels (>1 µM belinostat and >0.2 µM panobinostat) of AcH4 resulted in a significant inhibition of spontaneous as well as the NOX-dependent and -independent NETosis. By contrast, the degree of neutrophil apoptosis significantly increased, particularly in non-activated cells. Collectively, this study establishes that increasing concentrations of belinostat and panobinostat initially increases NETosis but subsequently reduces NETosis or switches the form of cell death to apoptosis. This new information indicates that belinostat and panobinostat can induce different types of neutrophil death and may induce neutropenia and regulate inflammation at different concentrations.
Project description:BACKGROUND:Maternal air pollution exposure has been related to orofacial clefts but the literature is equivocal. Potential chronic preconception effects have not been studied. OBJECTIVES:Criteria air pollutant exposure during three months preconception and gestational weeks 3-8 was studied in relation to orofacial defects. METHODS:Among 188,102 live births and fetal deaths from the Consortium on Safe Labor (2002-2008), 63 had isolated cleft palate (CP) and 159 had isolated cleft lip with or without cleft palate (CL ±CP). Exposures were estimated using a modified Community Multiscale Air Quality model. Logistic regression with generalized estimating equations adjusted for site/region and maternal demographic, lifestyle and clinical factors calculated the odds ratio (OR) and 95% CI per interquartile increase in each pollutant. RESULTS:Preconception, carbon monoxide (CO; OR=2.24; CI: 1.21, 4.16) and particulate matter (PM) ?10 µm (OR=1.72; CI: 1.12, 2.66) were significantly associated with CP, while sulfur dioxide (SO2) was associated with CL ±CP (OR=1.93; CI: 1.16, 3.21). During gestational weeks 3-8, CO remained a significant risk for CP (OR=2.74; CI: 1.62, 4.62) and nitrogen oxides (NOx; OR=3.64; CI: 1.73, 7.66) and PM ?2.5 µm (PM2.5; OR=1.74; CI: 1.15, 2.64) were also related to the risk. Analyses by individual week revealed that positive associations of NOx and PM2.5 with CP were most prominent from weeks 3-6 and 3-5, respectively. CONCLUSIONS:Exposure to several criteria air pollutants preconception and during early gestation was associated with elevated odds for CP, while CL ±CP was only associated with preconception SO2 exposure.